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Prostaglandin receptor agonists have intraocular pressure—lowering effects in humans and are of interest in the treatment of glaucoma. The prostanoid receptor agonist PF-04475270 is a potent and selective agonist of the prostaglandin E2 receptor EP4. This paper characterizes the toxicity associated with topical ocular administration of PF-04475270 in beagles. Dogs were given PF-04475270 topically to the eye on a consecutive daily dosing schedule for one or four weeks followed by a one- or four-week reversal period, respectively. Clinical observations, ophthalmic, and laboratory parameters were recorded. Necropsies were conducted at the end of the dosing and recovery phases, and histologic examinations performed. Corneal neovascularization that was considered adverse was observed at doses of ≥1.0 μg/eye and was not reversed by the end of the recovery phase. Dogs dosed with ≥0.25 μg/eye developed a dose-related conjunctival hyperemia that persisted throughout the reversal period. Corneal neovascular cells stained positive with EP4 and the endothelial biomarker Factor VIII-vWF. Other histopathology findings observed at doses of ≥1.0 μg included single-cell necrosis and neutrophils in the cornea, inflammatory cell infiltrates in the iris/ciliary body, and iridal endothelial cell hypertrophy. A resolving acute to subacute inflammation in the iris/ciliary body was observed after the four-week recovery period. [ABSTRACT FROM PUBLISHER]

Cyclin-dependent kinases (cdks) play a crucial role in cell cycle regulation and are considered promising targets for cancer therapy. Intravenous administration of AG-012986, a pan-cyclin-dependent kinase inhibitor (cdk i ), resulted in unexpected retinal and peripheral nerve toxicity in mice. AG-012986 was administered daily to CD-1 or B6C3F1 mice for 5 consecutive days. Mice were euthanized 24 h after the last dose (study day 6) or after a 21-day post-dose period (study day 26). Compound related microscopic findings were seen in the sciatic nerves (axonal degeneration) of both strains and in the retina (retinal degeneration/atrophy) of CD-1 mice only after the post-dose period. Although retinal degeneration/atrophy was not detected by routine histology in mice euthanized on day 6, apoptotic retinal cells were evident at this time using TUNEL assay. To our knowledge retinal or peripheral nerve toxicity secondary to the administration of cdk i s has not been previously reported. Although the pathogenesis of these lesions is unclear, the toxicities may reflect the unique profile of cdk inhibition, off-target kinase inhibition or receptor binding, or metabolism/distribution properties of AG-012986. Multi-targeted-inhibitors may interfere with cdks and other kinases involved in a wide range of functions other than cell cycle regulation, which could result in unexpected toxicities that may hinder their clinical applications. [ABSTRACT FROM AUTHOR]

The article describes lesions in preclinical studies produced by a pan-Cyclin Dependent Kinase (CDK) inhibitor (AG-12986) not previously reported. This class of compounds is currently an important component of the approach of targeted therapy against cancer. The Center for Disease Control has reported cancer as the second leading cause of mortality in the U.S.; it is expected to become the leading cause of death in this decade. Therapy against cancer continues its evolution, relying heavily on traditional DNA damaging agents or blockers of DNA synthesis. Many targeted therapies against cancer are focusing on one of the foundations of tumorigenesis, the cell cycle. Studies have shown that abnormal expression or function of molecules involved in the cell cycle are the origin of a variety of malignant neoplasms. Targeting the cell cycle controlling molecules is one of the most dynamic approaches for anticancer treatment.

Retina is a highly compact neural structure composed of distinct layers. The retinal pigmented epithelium (RPE) is the pigmented cell layer just outside the neurosensory and serves a number of crucial metabolic functions including the phagocytosis and removal of shed photoreceptor cell outer segments. Drugs with a basic moiety can accumulate in the lysososme and disturb lysosome function including phagocytosis, which will retard the clearance of outer segments and ultimately induce retinopathy. To test this hypothesis we chose a compound that contains a basic moiety and induced retinopathy in long term in vivo studies in rats In vitro assays including viability, LC-3 staining, and phagocytosis were conducted using the human retinal pigmented epithelium cell line ARPE-19. These studies showed that this compound caused cellular vacuolation and dose dependent cytotoxicity that was related to the initial cell number and dosing volume, indicating an accumulation effect. This compound also decreased phagocytosis function of ARPE-19, and induced accumulation of LC-3, suggesting a blockage of the autophagy process. EM analysis of eyes taken from an in vivo study showed the presence of large phagolysosomes, supporting the hypothesis of impairment of lysosome function as a mechanism for retinal toxicity. Twenty three proprietary compounds for which the in vivo effects on the retina were known were tested in a phagocytosis assay to examine the prevalence of this cellular mechanism in retinal toxicity. A correlation amongst the physiochemical properties, in vitro lysosomal pathway effects, and in vivo retinal effects was established. This data reveals the importance of physiochemical properties and lysosome accumulation as a common mechanism for drug induced retinopathy and demonstrates the potential usefulness of in vitro screening in predicting this liability. [ABSTRACT FROM AUTHOR]